Process for the preparation of substituted oxazolidones



United States Patent Oifice 3,528,976 PROCESS FOR THE PREPARATION OF SUBSTITUTED OXAZOLIDONES Manfred Budnowski, Dusseldorf-Holthausen, Germany,

assignor to Henkel & Cie, G.m.b.H., Dusseldorf-Holthausen, Germany, a corporation of Germany No Drawing. Filed July 19, 1966, Ser. No. 566,214 Claims priority, application Germany, June 24, 1966, H 59,753 Int. Cl. C07d 85/28, 87/40 [1.5. Cl. 260247.2 14 Claims ABSTRACT OF THE DISCLOSURE The present invention relates to novel oxazo idones- (2) substituted in the 5 position of the formula wherein R and R have the above-assigned meanings.

CLAIM FOR PRIORITY Applicant hereby claims the right of priority under 35 U.S.C. 119, based on the corresponding German application H 59,753, filed June 24, 1966.

THE PRIOR ART It is common knowledge, that S-substituted oxazolidomes-(2), for example S-(aryloxymethyl)-oxazolidones- (2) represent valuable sedatives and muscle relaxants. Various processes are known for the preparation of these oxazolidones. For the production of 5-(aryloxymethyl)- oxazolidones-(Z), for example the reaction of the corresponding phenylglycidylether with urea is well known. Analogous to this method of preparation it was to be anticipated, that glycidyl derivatives of secondary amines would yield also oxazolidones by reaction with urea. However, an attempt to react N-glycidylmorpholine with urea showed, that not the desired oxazolidones resulted, instead the reaction gave poylmer products, wherein no oxazolidone structures were observed by means of infrared spectroscopy. Consequently, this method for the preparation of the desired produtcs was rejected.

OBJECTS OF THE INVENTION wherein R and R are selected from the group consisting of organic groups free from epoxide-reacting s'ubstituents and, taken together, a bridging organic linkage free from epoxide-reacting substituents, said R and R having a total of from 2 to 30 carbon atoms.

A further object of the present invention is the devel- 3,528,976 Patented Sept. 15, 1970 opment of a process for the preparation of a S-substituted oxazolidone of the formula wherein R and R are selected from the group consisting of organic groups free from epoxide-reacting substituents and, taken together, a bridging organic linkage free form epoxide-reacting substituents, said R and R having a total of from 2 to 30 carbon atoms, which comprises reacting triglycidyl isocyanurate with a compound of the formula wherein R and R have the above-assigned meanings, at a temperature between about 60 C. and about 240 C and recovering said 5-substituted oxazolidone.

DESCRIPTION OF THE INVENTION These and other objects of the invention will become more apparent as the description thereof proceeds.

Now it has been discovered, that 5-substituted oxazolidones-(Z) can be obtained, when triglycidyl isocyanurate is reacted at elevated temperatures with an organic nitrogen compound, which contains on the nitrogen atom a hydrogen atom capable of reacting with epoxide compounds.

Utilizing as starting material, for example a secondary amine, the reaction of the invention proceeds according to the following over-all formula:

Suitable organic nitrogen compounds having a hydrogen atom on the nitrogen atom capable of reacting with epoxide compounds are, for example, secondary amines of the general formula R2 wherein R and R can be identical or different, if desired substituted, aliphatic, cycloaliphatic, aromatic hydrocarbon radicals or heterocyclic radicals. These compounds can contain as substitutents those which are able to react, not at all, or only slowly with the epoxide group under the reaction condition conditions. Such secondary amines may be: dialkylamines, such as dimethylamine, diethylamine, dibutylamine, ethyl-propylamine, dioctylamine, dodecylmethylamine, methylisopropylamine; alkylcycloalkylamines such as cyclohexylmethylamine; dicycloalkylamines such as dicyclohexylamine; diphenylamine; alkylheterocyclicamines such as methyltetrahydrofurfurylamine; dialkanol amines such as diethanolamine; alkylphenylamines such as methylaniline, N-ethyl- N-p-methoxyphenylamine, N-ethyl-p-chloroaniline, N- methyl-N-p-nitrophenylamine, etc. In the above basic formula for secondary amines, R and R can be selected from the group consisting of alkyl having from 1 to 18 carbon atoms, alkenyl having from 3 to 18 carbon atoms, hydroxyalkyl having from 2 to 18 carbon atoms, phenyl, halophenyl, lower alkoxyphenyl, nitrophenyl, and tetrahydrofurfuryl.

Other suitable organic nitrogen starting materials are, for example heterocyclic nitrogen compounds having a replaceable hydrogen atom on the nitrogen atom such as pyrrole, pyrroline, pyrrolidine, pyrazole, imidazole, the triazoles, benzimidazole, indole, piperidine, morpholine, theophylline, nornicotene and their derivatives. In the above basic formula R and R are taken together and represent an organic bridging linkage. The compounds react essentially as secondary amines. These compounds can likewise carry substituents, which under the reaction conditions in contact with epoxide compounds, are inactive or substantially less active than the replaceable hydrogen atom intended for the reaction.

Other suitable starting materials are, for example, straight-chain and cyclic sulfonic acid amides or carboxylic acid amides, which contain one reactive hydrogen atom on the nitrogen atom. To this class, be ong compounds such as p-toluene sulfonic acid methylamide, p-toluene sulfonic acid anilide, p-toluene sulfonic acid dodecylamide, p-toluene sulfonic acid oleylamide, 4- acetamido-benzene-sulfonic acid methylamide, p-acetamido benzene sulfonic acid-N-thiazolylamide, p-nitroacetanilide, p chloroacetanilide, N acetyl-p-toluidine, acetophenetidine, also sultams and lactams. In the above basic formula for amides, R can be selected from the group consisting of alkyl having from 1 to 18 carbon atoms, alkenyl having from 3 to 18 carbon atoms, alkanol having from 2 to 18 carbon atoms, phenyl, halophenyl, lower alkoxyphenyl, nitrophenyl, tetrahydrofurfuryl and thiazolyl; while R can be selected from the group consisting of the acyl of an organic carboxylic acid having from 2 to 18 carbon atoms and the acyl of an organic sulfonic acid having from 2 to 18 carbon atoms. The named and similar compounds may, in turn, carry any other substituents, which, under the reaction conditions, do not react at all or only slowly with epoxide compounds.

Furthermore, straight-chain or cyclic imides such as carboxylic acid-, sulfonic acidor mixed imides are to be considered as, for example, succinimide, phthalimide, maleic acid imide, o-sulfobenzoic acid imide (saccharin); disulfimides such as bis-(p-toluenesulfonyl)-imide, also hydantoin, 5,5-diphenyl-imidazolidine-dione-(2,4), theobromine, and their derivatives. These compounds too can carry substituents, which under the prevailing reaction conditions are either inactive or only slightly active with respect to epoxide compounds.

The triglycidyl isocyanurate, also serving as starting material, can be obtained, according to the processes described in the copending, comonly-assigned US. patent applications Ser. No. 288,593, filed June 18, 1963, now Pat. No. 3,288,789, or Ser. No. 467,140, filed June 25, 1965, now Pat. No. 3,300,490, in a simple manner in pure crystallized form from cyanuric acid and epichlorohydrin. Triglycidyl isocyanurate exists in two diastereomeric forms with difierent melting points (106 C. and 158 C.). Both forms can be employed either each by itself or admixed with each other for the present reaction.

The reaction is effected in that for each one mol of the triglycidyl isocyanurate, three mols of the respective, nitrogen containing compound are reacted. Consequently, it is of advantage to use the reactants at a ratio of about 1:3. Of course, the nitrogen containing compound can also be used in excess, advantageously up to about 6 mols to each mol of triglycidyl isocyanurate. This is particularly advantageous, when the nitrogen containing compound is easily volatile, so that the excess can be removed in a simple manner. It is less advisable to use the nitrogen containing compound in deficiency, because, as a rule,

admixtures of various reaction products are then obtained.

Advantageously, the reaction according to the present invention is carried out in an organic solvent. Suitable are, for example, benzene, toluene, chlorobenzene, dimethylformamide, dimethylsulfoxide, acetone and the like. It was noted that the reaction proceeds faster in polar solvents than in non-polar solvents. However, if the work is carried out with an excess of a basic nitrogen containing compound, no particular consideration is called for in regard to the choice of solvents.

In many cases it is advantageous to accelerate the reaction by adding small amounts of inorganic or organic bases. Suitable bases are, for example, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal lower alkylates such as sodium methylate and sodium ethylate; or tertiary organic bases such as dimethylaniline or dimethylbenzylamine. These compounds are active in relatively small amounts. In general, an addition of 0.001 to 0.1 equivalent of the bases indicated per one mol of the nitrogen containing compound will be sufiicient. However, if the reaction is conducted in those organic solvents, which simultaneously possess protonacceptor properties as, for example, dimethylsulfoxide, anisol, acetophenone, benzophenone, dimethylformamide, benzonitrile and acetonitrile, then a further addition of the above named bases is usually superfluous.

To conduct the reaction according to the invention,

for example, the triglycidyl isocyanurate and the nitrogen containing compound are dissolved in a suitable Organic solvent, and the reaction mixture, if so desired after adding a small amount of a base, is heated until the epoxideoxygen content of the solution has dropped to zero. Frequently it is advantageous to add the base only after the epoxide content has dropped to zero, as otherwise there exists the danger of polymerization of the triglycidyl isocyanurate. The reaction temperature may fluctuate within broad limits, for example, between about 60 C. and 240 C. In many cases it is advantageous to conduct the reaction under the reflux temperature of the organic solvent employed. Inasmuch as the reactants are not apt to decompose at elevated temperatures, the reaction may even be accomplished without any solvents. Moreover, it can be of advantage to add the triglycidyl socyanurate gradually to the dissolved nitrogen containing reactant heated to higher temperatures, as in this way a polymerization of the epoxide can be prevented.

After the reaction is completed, the solvent can be, if so desired, distilled off substantially under decreased pressure. The residue resulting from the evaporation is crystallized with suitable solvents such as alcohol, ether, water and others and, if necesary, recrystallized therefrom. In some cases, an intermediate step can be established 1n the reaction and the cyanurate reaction product converted into the desired oxazolidone in a second operation step. However, in many cases the reaction proceeds so rapidly that the intermediate cannot be isolated.

The following specific embodiments are illustrative of the invention. They are not, however, to be deemed limitative in any respect.

Example 1 15 gm. of the high-melting (,B-form) cyanurate and 20 gm. of diethylamine were stirred together with 200 ml. of nitrobenzene and 0.5 gm. of potassium hydroxide for 5 hours at 150 C. After this period no epoxide-oxygen content was evident any more. Next, the solvent was distilled under decreased pressure. The residue was several times recrystallized from benzin (B.P. C. to C.) with an addition of about 5% of ether. The yield of S-(diethylaminomethyl)-oxazolidone-(2), after five recrystallizations, amounted to 14 gm. (67% of the theory). The product had a melting point of about 70 C.

Analysis.Calculated for C H N O (percent): C,

of triglycidyl iso- 55.8; H, 9.4; N, 16.3. Found (percent): C, 55.4; H, 9.6; N, 15.9.

Example 2 29.7 gm. of the high-melting (B-form) of triglycidyl isocyanurate and 64.2 gm. of methylaniline were stirred together with 400 ml. of nitrobenzene and 0.5 gm. of sodium hydroxide over a period of hours at 150 C. After this time, no epoxide-oxy-gen content was evident anymore. Then the solvent was distilled therefrom under decreased pressure. The resultant residue consisted of a viscous syrup, the oxazolidone structure of which was determined by infra-red-analysis. A sample of 20 gm. was recrystallized five times from an ether/petroleum ether mixture. The melting point of the thus purified 5- [(N-methyl-N-phenyl) -aminomethyl] oxazolidone (2) was 73 C. The yield amounted to 12 gm. corresponding with 59% of the theory.

Analysis.-Calculated for C H N O (percent): C, 64.1; H, 6.8; N, 13.6; M.W., 206. Found (percent): C, 64.2; H, 6.9; N, 13.2; M.W., 191.

Example 3 30 gm. of the high-melting (p-form) of triglycidyl isocyanurate were heated together with 81 gm. of pnitroacetanilide and 300 ml. of dimethylforamide to 140 C. while stirring. 0.5 gm. of sodium hydroxide were added to the mixture. After a reaction period of 4 hours at 140 C., the epoxide-oxygen content of the solution had dropped to zero. After being cooled to room temperature, the solvent was distilled therefrom, to a great extent, under decreased pressure. The resultant residue (111 gm.) was extracted twice with water. After concentration of the aqueous phase, a residue remained, which was recrystallized twice from ethanol.

The yield in N-(p-nitrophenyl)-N-[(oxazolidone-(2)- yl-(5))-methyl]-acetamide amounted to 56 gm. corresponding with 68% of the theory. The substance started to sinter at a temperature of 177 C. and was completely melted at 181 C.

Analysis.-Calculated for C H N O (percent): C, 51.6; H, 4.7; N, 15.1; M.W., 279. Found (percent): C, 52.0; H, 5.1; N, 15.0; M.W., 269.

Example 4 29.7 gm. of the low-melting (or-form) of triglycidyl isocyanurate and 44.5 gm. of phthalimide were heated together with 400 ml. of chlorobenzene and 200 mg. of sodium hydroxide at reflux for 1% hours. After this period no epoxide-oxygen content was evident anymore. Subsequently, most of the solvent was distilled 01f at decreased pressure. The residue was recrystallized from a water/ethanol mixture (1:1). 65 gm., that is 88% of theory, of S-(phthalimidomethyl)-oxazolidone-(2) were obtained, the product having a melting point of 184 C.

Analysis.Calculated for C H N O (percent): C, 58.5; H, 4.1; N, 11.4; M.W., 246. Found (percent): C, 58.7; H, 4.1; N, 11.0; M.W., 244.

Example '5 29.7 gm. of the high-melting (fit-form) of triglycidyl isocyanurate and 5 6 gm. of p-toluenesulfonic acid methylamide were heated, together with 500 ml. of toluene and 300 mg. of pulverized sodium hydroxide, at reflux for 5 hours. After this period, the epoxide-oxygen content of the solution had dropped to zero. Then most of the solvent was distilled off under decreased pressure (water-jet pump). The residue was recrystallized from benezene. 70 gm. (that is 82% of theory) of N-methyl- N [(oxazolidone-(2)-yl-(5))-methyl] p toluene-sulfonamide were obtained. The product had a melting point of 121 C.

Analysis-Calculated for C H N O S (percent): N, 9.9; S, 11.2; M.W., 284. Found (percent): N, 10.2; S, 11.0; M.W., 307.

6 Example 6 29.7 gm. of the high-melting (pr-form) of triglycidyl isocyanurate and 55 gm. of saccharin (2,3-dihydro-3- oxobenzisosulfonazole) were heated, together with one liter of chlorobenzene and 300 mg. of sodium hydroxide, at reflux. After 14 hours the epoxide-oxygen content of the solution had dropped to zero. Thereafter, most of the solvent was distilled off under decreased pressure, the residue was taken up in chloroform and precipitated with ether.

After triple reprecipitation, the yield of N-([oxazolidone-(2)-yl-(5)]-methyl)-saccharin amounted to 40 gm. (47.5% of the theory). The product obtained had a melting point of 136 C.

Analysis.--Calculated for C H N O S (percent): N, 9.9%; S, 11.3. Found (percent): N, 9.8; S, 11.0.

Example 7 29.7 gm. of the low-melting (ct-form) of triglycidyl isocyanurate and 28 gm. of piperidine were heated, together with 350 m1. of toluene and 250 mg. of sodium hydroxide for 1 hour at reflux. After this time the epoxideoxygen content had dropped to zero. The purification of the mixture was effected by recrystallization of the evaporation residue from ethyl acetate.

The yield of the S-piperidinomethyl-oxazolidone-(2), having a melting point of 114 C., amounted to 48 gm. (87% of the theory).

Analysis.Calculated for C H N O (percent): C, 58.7; H, 8.7; N, 15.2; M.W., 184. Found (percent): C, 59.0; H, 8.8; N, 14.9; M.W., 183.

Example 8 29.7 gm. of the low-melting (or-form) of triglycidyl isocyanurate and 27 gm. of morpholine were heated, together with 350 ml. of toluene and 250 mg. of sodium hydroxide, at reflux for 1 hour. After this period of time no epoxide-oxygen content was evident anymore. The purification of the mixture was effected by a single recrystallization of the precipitation product from toluene. The yield of 5 morpholinomethyl oxazolidone (2) amounted to 52 gm. (92% of the theory). The product had a melting point of 124 C.

Analysis.Calculated for C H N O (percent): C, 51.6; H, 7.6; N, 15.0; M.W., 186. Found (percent): C, 51.6; H, 7.7; N, 15.1; M.W., 176.

Example 9 This example proves that it is often possible to isolate the adduct formed in the first step by means of reaction of the nitrogen containing compound with triglycidyl isocyanurate, and then, in a second step to effect the cyclization to oxazolidone with the addition of a base.

29.7 gm. of triglycidyl isocyanurate (fl-form) were heated, together with 27 gm. of morpholine, for 3 hours at reflux in 300 ml. of toluene. After this time the test for epoxide-oxygen content was negative. While the reaction solution was cooling, a crystalline precipitate formed, which, after being filtered and Washed once with cold toluene, had a melting point of 168 C. The yield in tris (2-hydroxy-3-N-morpholine-propyl) isocyanurate amounted to 54 gm. (96% of the theory).

This isocyanurate was again heated, in a second reaction stage, at reflux for 10 hours in 300 ml. of toluene, in the presence of 30 mg. of sodium hydroxide. After the reaction mixture had been cooled, the crystallized 5- morpholino-methyl-oxazolidone-(2) was filtered and re crystallized from benzene. The product, which was identical to the one obtained by the process described in Example 8, had a melting point of 124 C. The yield amounted to 43 gm. of product (75% of the theory).

Example 10 29.7 gm. of the high-melting (ii-form) of triglycidyl isocyanurate and 50.0 gm. of di-n-butylamine were heated together with 500 ml. of chlorobenzene 500 mg. of sodium hydroxide at reflux for 7 hours. After this period no epoxide-oxygen content was evident anymore. After being cooled to room temperature the reaction solution was filtered and the solvent was distilled therefrom under decreased pressure. The residue was crude S-(di-n-butylaminomethyl)-oxaZolidone-(2) in a yield of 59 gm. (86% of the theory). After distillation under decreased pressure the yield of the pure product amounted to 51 gm. (74.6% of the theory). The product obtained had a boiling point of 161 C. at a pressure of 0.2 torrv Analysis.Calcu-lated for C H N O (percent): C, 63.1; H, 10.5; N, 12.3. Found (percent): C, 63.4; H, 10.7; N, 12.0.

The products obtained according to the process of the invention are valuable pharmaceutics.

The invention process renders it possible to combine the pharmacologically active oxazolidone group in a very careful way with other pharmacologically active groups, for example with the sulfonamide groups to obtain the combined pharmacological eifectiveness of both active groups.

The advantage, which is obtainable on hand of the invention, consists in particular in that accordingly oxazolidones can be prepared from those reactants, which are thermically sensitive as for example morpholine, and for which other oxazolidone syntheses fail for this very reason.

The products produced are useful as sedatives and muscular relaxants, in general at low dosages.

The preceding specific embodiments are illustrative of the practice of the invention. It is to be understood however that other expedient, as would occur to those skilled in the art, may be employed without departing from the spirit of the invention.

I claim:

1. A process for the production of a -substituted oxa- Zolidone of the formula wherein R is selected from the group consisting of alkyl having from 1 to 18 carbon atoms, alkenyl having from 3 to 18 carbon atoms, hydroxyalkyl having from 2 to 18 carbon atoms, phenyl, halophenyl, lower alkoxyphenyl, nitrophenyl and tetrahydrofurfuryl and R is selected from the group consisting of alkyl having from 1 to 18 carbon atoms, alkenyl having from 3 to 18 carbon atoms, hydroxyalkyl having from 2 to 18 carbon atoms, phenyl, halophenyl, lower alkoxyphenyl, nitrophenyl alkanoyl having from 2 to 18 carbon atoms and arylsulfonyl having from 7 to 18 carbon atoms, and where R and R taken togteher with the nitrogen atom, are selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, arylene dicarboxylic acid imdo arylene dsulfonic acid imido and arylene mono-carboxylic acid-mono-sulfonic acid mixed imido; where R and R have a total of from 4 to 30 carbon atoms, which comprises reacting triglycidyl isocyanurate wth a compound of the formula wherein R and R have the above-assigned values and H represents a hydrogen atom capable of reacting with an epoxide compound, at a temperature between about 60 C. and about 240 C., and recovering said 5-substituted oxazolidone.

2. The process of claim 1 wherein said reaction is conducted in the presence of an organic solvent.

3. The process of claim 2 wherein said organic solvent is a proton acceptor.

4. The process of claim 1 wherein said reaction is conducted in the presence of small amounts of bases selected from the group consisting of inorganic bases and tertiary organic bases.

5. The process of claim 1 wherein from 3 to 6 mols of the compound are employed per mol of triglycidyl isocyanurate. 6. A S-substituted oxazolidone of the formula CH2NH wherein R is selected from the group consisting of alkyl having from 1 to 18 carbon atoms, alkenyl having from 3 to 18 carbon atoms, hydroxyalkyl having from 2 to 18 carbon atoms, phenyl, halophenyl, lower alkoxyphenyl, nitrophenyl and tetrahydrofurfuryl and R is selected from the group consisting of alkyl having from 1 to 18 carbon atoms, alkenyl having from 3 to 18 carbon atoms, hydroxyalkyl having from 2 to 18 carbon atoms, phenyl, halophenyl, lower alkoxyphenyl, nitrophenyl, alkanoyl having from 2 to 18 carbon atoms and arylsulfonyl having from 7 to 18 carbon atoms, and where R and R taken together with the nitrogen atom, are selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl, arylene dicarboxylic acid imido, arylene disulfonic acid imido and arylene mono-carboxylic acid-mono-sulfonic acid mixed imido; where R and R have a total of from 4 to 30 carbon atoms.

7. The process of claim 6 wherein R and R are butyl.

8. The process of claim 6 wherein R is methyl and R is phenyl.

9. The process of claim 6 wherein R is p-nitrophenyl and R is acetyl.

10. The process of claim 6 wherein R is methyl and R is p-toluene sulfonyl.

11. The process of claim 6 wherein R and R taken together with the nitrogen atom is piperidinyl.

12. The process of claim 6 wherein R and R taken together with the nitrogen atom is morpholinyl.

13. The process of claim 6 wherein R and R taken together with the nitrogen atom is phthalimido.

14. The process of claim 6 wherein R and R taken together with the nitrogen atom is o-sulfobenzoylimido.

References Cited UNITED STATES PATENTS 3,108,115 10/1963 Little et al 260-307 3,231,577 l/1966 Walles 260-307 FOREIGN PATENTS 1,085,106 9/1967 Great Britain.

OTHER REFERENCES Weissberger: The Chemistry of Heterocyclic Compounds, vol. 19, Part one (Interscience, N.Y., 1964), pages 316-318.

ALTON D. ROLLlNS, Primary Examiner U.S. Cl. X.R. 

